Copper-Catalyzed Highly Stereoselective Trifluoromethylation and Difluoroalkylation of Secondary Propargyl Sulfonates

Article abstract of DOI:10.1002/anie.201711463

It is challenging to stereoselectively introduce a trifluoromethyl group (CF₃) into organic molecules. To date, only limited strategies involving direct asymmetric trifluoromethylation have been reported. Herein, we describe a new strategy for direct asymmetric trifluoromethylation through the copper-catalyzed stereospecific trifluoromethylation of optically active secondary propargyl sulfonates. The reaction enables propargylic trifluoromethylation with high regioselectivity and stereoselectivity. The reaction could also be extended to stereospecific propargylic difluoroalkylation. Transformations of the resulting enantiomerically enriched fluoroalkylated alkynes led to a variety of chiral fluoroalkylated compounds, thus providing a useful protocol for applications in the synthesis of fluorinated complexes.

Full text of DOI:10.1002/anie.201711463

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Accepted Article
Title: Copper-Catalyzed Highly Stereospecific Trifluoromethylation and
Difluoroalkylation of Secondary Propargyl Sulfonates
Authors: Xingang Zhang, Xing Gao, Yu-Lan Xiao, and Xiaolong Wan
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201711463
Angew. Chem. 10.1002/ange.201711463
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COMMUNICATION
Copper-Catalyzed Highly Stereospecific Trifluoromethylation and
Difluoroalkylation of Secondary Propargyl Sulfonates**
Xing Gao, Yu-Lan Xiao, Xiaolong Wan, and Xingang Zhang*
Abstract: It is challenging to stereoselectively introduce
a
and efficient to construct chiral C-C bonds,[10] it remains a
formidable challenge to directly adapt these strategies and
access enantioenriched trifluoromethylated compounds, mostly
due to the lack of efficient catalytic system. To the best of our
trifluoromethyl group (CF ) into organic molecules that can be
3
readily transformed into versatile compounds. To date, only limited
strategies through direct asymmetric trifluoromethylations have
been reported. Here, we describe a new strategy for direct
knowledge,
the
asymmetric
transition-metal-catalyzed
asymmetric
trifluoromethylation
through
copper-catalyzed
trifluoromethylation reaction has not been reported thus far.
As part of our ongoing study on transition-metal-catalyzed
fluoroalkylation reactions,[11] herein, we demonstrate the
feasibility of stereoselective copper catalyzed propargylic
trifluoromethylation, in which the versatile synthetic utility of
carbon-carbon triple bond can be applied in the synthesis of
biologically active molecules and advanced functional
materials. In this study, we focused our research on addressing
three crucial issues of this reaction: (1) efficient catalytic system
stereospecific trifluoromethylation of optically active secondary
propargyl sulfonates. The reaction enables the propargylic
trifluoromethylation with high regioselectivity and stereospecificity.
The reaction can also be extended to stereospecific propargylic
difluoroalkylation. Transformations of the resulting enantioenriched
fluoroalkylated alkynes led to a variety of chiral fluoroalkylated
compounds, providing a useful protocol for applications in the
synthesis of fluorinated complexes.
to stereoselectively construct C-CF
selectivity, i.e., propargylic trifluoromethylation vs. allenic
trifluoromethylation. Previously, the copper-catalyzed
trifluoromethylation of secondary propargylic compounds
always led to the trifluoromethylated allenes as the major
products;[12] (3) broad substrate scope.
3
bond; (2) regiochemical
Due to the unique characteristics of fluorine atom(s) and C-
F bond(s), fluorine-containing organic compounds have been
extensively applied in life and materials science,[1] and continue
to receive increasingly demanding requirements in terms of
precise molecule engineering, i.e., enabling to introduce
fluorine atom(s) into organic molecules at desirable position
with high stereoselectivity in a highly controllable manner. Over
the past decade, despite of great achievements in the
Initially, we began our studies by choosing secondary
propargyl sulfonate 1 as a model substrate to construct the
trifluoromethylated stereogenic center [eq 1]. The use of
triisopropylsilyl (TIPS) as a protecting group for the alkyne 1 is
because of its steric effect that can suppress the allenic side
products.[13] After extensive efforts, we found that a range of
enantiopure ligands, such as box, pybox, phox, taddol and
binam only provided racemic products 3; the use of nonchiral
ligands, such as bpy and phen totally inhibited the reaction (for
details, see the Supporting Information). It is worth noting that
[2]
construction of Ar-F and Ar-R
direct asymmetric fluoroalkylations are far less explored.
As a distinct fluoroalkyl moiety, trifluoromethyl group (CF
f f
(R = fluoroalkyl) bonds, the
[
3]
3
)
appears in numerous pharmaceuticals, agrochemicals and
advanced functional materials, especially, many therapeutic
drugs contain a trifluoromethylated stereogenic center that are
-containing substrates.[4] To
usually formed from prochiral CF
3
the
absence
of
ligand
benefited
the
propargylic
date, however, only limited strategies through direct asymmetric
trifluoromethylation have been reported, many of which focused
trifluoromethylation, providing 3a in a good yield (80%) along
with small amount of allenic side product (2% yield). This
finding suggested that employment of an enantioenriched
on
organocatalyzed
enantioselective
nucleophilic
[
3, 5]
imines[6] and
trifluoromethylation of ketones (aldehydes),
active Morita-Baylis-Hillman (MBH) carbonates. The catalytic
enantioselective electrophilic[8] or radical[9] -trifluoromethylation
[
7]
substrate
trifluoromethylated product 3a.
1a
might
provide
an
enantioenriched
[
14]
of carbonyl compounds has also proved to be useful strategies
to prepare enantioenriched trifluoromethylated compounds.
Despite of importance of these methods, they are all restricted
to the fuctionalization of carbonyl compounds. To extend the
synthetic structure diversity, the asymmetric transition-metal-
catalyzed trifluoromethylation would be a promising alternative
to the above methods. Although the transition-metal-catalyzed
cross-coupling reactions have proved to be powerful, practical
However, the previous copper-catalyzed trifluoromethylation
of optically pure propargylic compounds afforded unfavorable
racemic allenic products via cationic propargyl/allenyl-copper
complexes involved pathway.[12b] To circumvent this challenge,
we hypothesized that if a suitable leaving group at the
propargylic position could enable the oxidative addition of
copper to C-X (X, leaving group) bond without racemization, the
asymmetric trifluoromethylation would be feasible. Accordingly,
a series of leaving groups were examined by reaction of
enantioenriched propargylic substrates S-1 (99% ee) with
[]
X. Gao, Y.-L. Xiao, X. Wan, Prof. Dr. X. Zhang
Key Laboratory of Organofluorine Chemistry
Center for Excellence in Molecular Synthesis
Shanghai Institute of Organic Chemistry
University of Chinese Academy of Sciences
Chinese Academy of Sciences
[
15]
345 Lingling Lu, Shanghai 200032 (China)
TMSCF
in the presence of CuCN (10 mol %) in DME at 70
3
Fax: (+) 86-21-64166128
E-mail: xgzhang@mail.sioc.ac.cn
o
C (Table 1, entries 1-5). The optically active S-1 can be readily
prepared by asymmetric synthesis of propargylic alcohol,[
followed by protection.
16]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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COMMUNICATION
Table 1. Representative results for the optimization of stereospecific copper-
bromides were still compatible with the reaction conditions (3f
and 3k), thus highlighting the advantages of current reaction
further. What is more, amino acid-containing substrate was also
catalyzed propargylic trifluoromethylation.[a]
a
competent coupling partner without influence of the
enantiospecificity (3m). In light of the importance of fluorinated
amino acids and their derivatives in modification of peptides
based biologically active molecules and protein engineering,[
this transformation offers potential applications in medicinal
chemistry and chemical biology. The reaction conditions are
readily scalable as demonstrated by the gram-scale synthesis
of 3n with high efficiency and excellent enantiospecificity (es,
18]
yield [%],[b] 3a / 4a
Entry
1, LG
[Cu]
1
1a, pMeO-PhSO
2
CuCN
CuCN
CuCN
CuCN
CuCN
CuCN
None
83[e] (97) / 2
2[c]
1b, pMe-PhSO
1c, p-tBu-PhSO
1d, pNO -PhSO
1e, MeSO
2
----
----
----
3[c]
2
0.98; 96% ee). Notably, the reaction can also be conducted at
4[c]
room temperature by expanding the reaction time to 72 h as
demonstrated by the synthesis of compound 3b. However, the
replacement of TIPS with less hindered silyl groups (e.g.
trimethylsilyl (TMS), triethylsilyl (TES) or tert-butyldimethylsilyl
2
2
5
2
71[e] (97) / 2
6[d]
90[e, f] (97) / trace
1a, pMeO-PhSO
1a, pMeO-PhSO
2
2
(
TBDMS)), phenyl group or hydrogen resulted in a mixture of
7
n.d.
propargylic and allenic products or no product 3 (for details, see
the Scheme S2 in the Supporting Information). Thus, these
results demonstrate that the presence of TIPS group on the
secondary proparyl sulfonates is essential for the current
stereospecific propargylic trifluoromethylation. We also
examined other secondary sulfonates, such as benzyl and allyl
sulfonates. But they all failed to provide corresponding
trifluoromethylated products because of the instability of the
substrates (for details, see the Scheme S3 in the Supporting
Information).
[
2
a] Reaction conditions (unless otherwise specified): 1 (0.3 mmol, 1.0 equiv),
(0.45 mmol, 1.5 equiv), DME (2 mL), 12 h. [b] Determined by 19F NMR
using fluorobenzene as an internal standard; numbers in parentheses are ee
values. [c] Compounds 1b-d are unstable and the yields of 3a were not
determined. [d] Reaction run at 40 oC for 24 h. [e] The es of 3a is 0.98. es =
eeproduct/eestarting material. [f] Isolated yield.
Among
the
tested
leaving
groups,
para-
methoxybenzenesulfonate 1a showed beneficial effect and
provided 3a in an 83% yield with a high ee value (97% ee) and
excellent enantiospecificity (es, 0.98) (entry 1), in striking
contrast to previous results,[12b] in which a racemic allenic
product was obtained. The use of tosylate and other
aylsulfonates bearing tert-butyl or electron-deficient group
resulted in unstable proparylic sulfonates 1c and 1d (entries 2-
Table 2. Scope of the copper-catalyzed stereospecific propargylic
trifluoromethylation.[a]
4), which were prone to formation of enyne upon purification
with silica gel chromatography. We found that the mesylate was
also a good leaving group, providing 3a in a 71% yield with
excellent enantiospecificity (es, 0.98) (entry 5). However, its
corresponding proparylic sulfonate 1e is less stable than 1a.
Other leaving groups, such as acetate, pivalate, trifluoroacetate
and phosphonate led to no 3a (see the Supporting
Information).[ The reaction was not sensitive to the copper
17]
source and
a series of copper(I) salts provided 3a in
comparable yields (for details, see the Supporting Information).
Further optimization of the reaction conditions showed that
ethereal solvents benefited the reaction, while other solvents
including DMF, CH CN and toluene resulted in low yields or no
3
product (for details, see the Supporting Information). Finally, an
optimal yield (90% yield upon isolation) of 3a with 97% ee and
0
.98 es was obtained by decreasing the reaction temperature to
o
40 C with 1a as a substrate, CuCN as a catalyst and DME as a
solvent (entry 6). The absence of copper failed to afford 3a
entry 7), thus demonstrating that copper is essential in
(
promotion of the reaction.
[
2
a] Reaction conditions (unless otherwise specified): 1 (0.3 mmol, 1.0 equiv),
With the viable reaction conditions in hand, a variety of
optically active propargyl sulfonates S-1 were examined (Table
(0.45 mmol, 1.5 equiv), DME (2 mL), 24 h. [b] Reaction was conducted at
o
room temperature for 72 h. [c] 2 (2.0 equiv), CuCN (15 mol %), 70 C, DME
2). Generally, the reaction showed excellent enantiospecificity
(2 mL), 12 h.
(
es, 0.94-0.99) and moderate to excellent yield (62-93%).
In addition to demonstrating the scope of this reaction, we
investigated the stereospecific propargylic difluoroalkylation
Substrates bearing a furranyl, alkenyl, benzyloxyl, ester, cyano
and dialkylamine group exhibited excellent tolerance to the
current copper-catalyzed process (3d, 3e, 3g-3j, 3l).
Remarkably, the good chemoselectivity with an intact alkyl
sulfonate moiety provided good opportunities for the
downstream transformations (3n). Even the alkyl and aryl
(
Table 3) and chose trimethylsiyldifluoroamide 6 as a
difluoroalkylating reagent for the current copper-catalyzed
process, because difluoroamide moiety appears in several
biological active molecules[ and can serve as a versatile
19]
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COMMUNICATION
functional group (Table 3). However, no product 5a was
obtained when S-1 was treated with 6 under standard reaction
conditions. Switching DME to DMF benefited the reaction and a
approach to access enantioenriched trifluoromethylated alkynes
(10c). Furthermore, the transformation of
successfully conducted on the aliphatic chain as demonstrated
by nucleophilic substitution of aliphatic sulfonate 8 with NaN
3
8
could be
67% yield of 5a with 99% ee and >0.99 es was provided when
3
0 mol% of CuCN was used.
(10d). Transformations of 9 also furnished corresponding
enantioenriched difluoroalkylated compounds efficiently. As
shown in Scheme 1c, selective hydrogenation of 9 led to
enantioenriched allylic difluoroalkylated compound 11 with high
efficiency. Dihydroxylation of 11 afforded chiral diol 12 in a
synthetically useful yield with excellent diastereoselectivity (dr >
Table 3. Scope of the copper-catalyzed stereospecific propargylic
difluoroalkylation.[a]
99:1).
Scheme 1. Transformations of compounds 3n and 5c
The absolute configuration of final enantioenriched
fluoroalkylated compounds was determined to be R by X-ray
crystal structure analysis of compound 3b, 3e and 5b,[
which were derived from compound 3b, 3e and 5b, respectively,
through a [3+2] cyclization with benzyl azide (Scheme 2a). In
view of the fact that usually, the transmetalation and reductive
21]
[
6
a] Reaction conditions (unless otherwise specified): 1 (0.3 mmol, 1.0 equiv),
(0.6 mmol, 2.0 equiv), DMF (2 mL), 12 h.
Under the optimal reaction conditions,
a variety of
propargylic sulfonates S-1 underwent the difluoroalkylation
reactions smoothly with high ee values and stereospecificities
(
compatibility (5d-5j) and high chemo-regioselectivity were
observed (5d, 5g and 5h). It should be mentioned that it is hard
to access these enantioenriched difluoroalkylated compounds
through conventional methods, thus demonstrating the
advantages of current approach further.
[22]
elimination are known to occur with retention of configuration,
we envisioned that an inversed configuration was occurred in
the course of the oxidative addition of copper to the secondary
propargyl sulfonates, which was consistent with previous
es, 0.93
–
>0.99). Again, excellent functional group
[23]
reports for the palladium-catalyzed reactions. On the basis of
above results and previous reports on the copper-mediated
trifluoromethylation,[2b, c] a plausible reaction mechanism was
proposed (Scheme 2b). The reaction began with the formation
The importance and utility of this protocol can also be
highlighted by the synthesis of diverse enantioenriched
trifluoromethylated and difluoromethylenated molecules from
compounds 3n or 5c. As shown in Scheme 1a, the TIPS group
was readily deprotected by treatment of 3n or 5c with TBAF in
of trifluoromethylcopper complex
A between CuCN and
TMSCF . The resulting A underwent oxidative addition with
3
secondary propargyl sulfonate 1 to afford a configuration
inversed propargyl Cu(III) species B. After a retentive reductive
elimination of B, the final trifluoromethylated product 3 was
produced with inverse of configuration.
o
THF at -20 C, but higher reaction temperature would lead to
some uncertain by-products. The resulting terminal alkynes 8
and 9 can serve as versatile building blocks for the synthesis of
a variety of enantioenriched fluoroalkylated compounds that are
difficult to access through conventional methods. For example,
hydrogenation of 8 afforded enantioenriched trifluoromethylated
alkane 10a in a high yield without erosion of the ee value, thus
offering an efficient route for site-selective introduction of a
trifluoromethylated stereogenic center into an aliphatic chain
(
Scheme 1b). The alkynyl moiety could also be employed for
the construction of heterocycle through a [3+2] cyclization[20] to
combine an N-heterocycle and chiral trifluoromethyl, two
essential moieties for medicinal chemistry, into one molecule
(
10b). Additionally, the Sonogashira reaction of
8 with
Scheme 2. Determination of absolute configuration of compounds 3 and 5
and proposed reaction mechanism.
heteroaryl iodide proceeded smoothly, providing an alternative
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COMMUNICATION
In conclusion, we have developed the first example of
copper-catalyzed stereospecific trifluoromethylation and
difluoroalkylation of secondary propargyl sulfonates. The
reaction proceeded under mild reaction conditions with high
regioselectivity and stereospecificity (es up to >0.99), broad
substrate scope as well as excellent functional group
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enantioenriched
131, 10875.
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9
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Acknowledgements ((optional))
[14]
Only one example of photoredox catalyzed trifluoromethylation of
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This work was financially supported by the National Natural
Science Foundation of China (No. 21425208, 21672238,
2
170225, 21332010, and 21421002), the National Basic
Research Program of China (973 Program) (No.
015CB931900), the Strategic Priority Research Program of
2
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[18]
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difluoroalkylation
•
secondary propargyl sulfonates
•
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Angewandte Chemie International Edition
10.1002/anie.201711463
COMMUNICATION
COMMUNICATION
Xing Gao, Yu-Lan Xiao, Xiaolong Wan,
and Xingang Zhang*
Page No. – Page No.
Copper-Catalyzed Highly
Stereospecific Trifluoromethylation
and Difluoroalkylation of Secondary
Propargyl Sulfonates
Text for Table of Contents
Chiral conversion: A title reaction has been developed (see Scheme). The reaction enables the propargylic trifluoromethylation and
difluoroalkylation with high regioselectivity and stereospecificity. An inversed configuration was observed for current copper-
catalyzed process, demonstrating that a S
the reaction.
N
2 type oxidative addition of copper to secondary propargyl sulfonates may be involved in
This article is protected by copyright. All rights reserved.